Abstract
Epidemiological studies have shown that diabetes mellitus and obesity are risk factors for the genesis and progression of Alzheimer's disease. In the last decade, studies have demonstrated the existence of brain insulin resistance in Alzheimer's disease (AD) patients, suggesting that a reduced glucose uptake to neuronal cells could be a key element in the onset and progression of neurodegeneration in AD. In hippocampal neurons, a region that is severely compromised in AD, the presence of the glucose transporter isoform 4, codified by the SLC2A4 gene the same that is expressed in adipose and muscular tissues, has been suggested to be repressed in states of insulin resistance and/or diabetes. Neuroinflammation, possibly mediated by some factors such as amyloid beta peptide accumulation and advanced glycation end-products, has also been related to the etiopathogenesis of AD. Our group has already demonstrated that inflammatory activity is a potent repressor of the SLC2A4 gene in peripheral tissues, but nothing is known in central areas. Furthermore, recent studies suggest that epigenetic mechanisms can regulate the transcription of genes important in the pathophysiology of AD; and we have already shown epigenetic changes in the SLC2A4 gene in the muscle of diabetic rats, but nothing is known about it in the brain. Thus, the aim of this project is to investigate, in the hippocampus of (postmortem) brains of obese humans, whether diabetes alters the expression of SLC2A4/ GLUT4 and inflammatory markers. In addition, in neurons cultured in conditions that mimic diabetes challenges, molecular mechanisms potentially related to changes in SLC2A4 transcription, such as inflammatory and epigenetic mechanisms, will be investigated. The results obtained are expected to determine the participation of SLC2A4/GLUT4 in the pathophysiology of Alzheimer's disease, as well as the power of diabetes to exacerbate these mechanisms, grounding new preventive and/or therapeutic principles for Alzheimer's disease to be developed in the future.
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